Solubilization of a poorly water-soluble drug is a key technology for delivering the drug into the body via oral or parenteral administration. Such solubilization methods include a method of adding a surfactant to an aqueous solution to form micelles and then entrapping a poorly water-soluble drug therein.
An amphiphilic block copolymer used as a surfactant comprises a hydrophilic polymer block and a hydrophobic polymer block. Since the hydrophilic polymer block directly contacts blood proteins and cell membranes in vivo, polyethylene glycol or monomethoxypolyethylene glycol, etc. having biocompatibility has been used. The hydrophobic polymer block improves affinity to a hydrophobic drug, and polylactide, polyglycolide, poly(lactic-glycolide), polycaprolactone, polyamino acid or polyorthoester, etc. having biodegradability has been used. In particular, polylactide derivatives have been applied to drug carriers in various forms because they have excellent biocompatibility and are hydrolyzed into harmless lactic acid in vivo. Polylactide derivatives have various physical properties depending on their molecular weights, and have been developed in various forms such as microsphere, nanoparticle, polymeric gel and implant agent.
U.S. Pat. No. 6,322,805 discloses a composition for delivering a poorly water-soluble drug consisting of a polymeric micelle-type drug carrier and a poorly water-soluble drug, wherein the polymeric micelle-type drug carrier is formed from a diblock or triblock copolymer which is not crosslinked by a crosslinking agent and consists of at least one biodegradable hydrophobic polymer selected from the group consisting of polylactide, polyglycolide, poly(lactide-glycolide), polycaprolactone and derivatives thereof and poly(alkylene oxide) as a hydrophilic polymer, wherein the poorly water-soluble drug is physically entrapped in the drug carrier and solubilized, and wherein the polymeric micelle-type drug carrier forms a clear aqueous solution in water and effectively delivers the poorly water-soluble drug into the body.
However, the above pharmaceutical composition comes to have an increased amount of related substances with the lapse of storage time. To analyze the related substances in the composition, an analysis method of using C18 column has been used, but it does not have a sufficient resolution to isolate some related substances. In particular, since the resolution of 10-deacetyl-7-epipaclitaxel (impurity B)—which is one of the representative related substances of paclitaxel—and paclitaxel is 0.95 or lower, they are not completely isolated and there has been a need to improve the resolution. In addition, the two unknown impurities shown at relative retention time (RRT) 1.14 as the related substances observed during the long-term storage test for six months or longer or the severe condition test are detected as one peak, not being isolated from each other. Furthermore, in order to analyze a very small amount of related substance with a similar method, the injection amount of the sample must be increased largely as compared with one for content test.
Accordingly, there has been a need to develop an analysis method which can isolate the impurities in the course of production and marketing of the pharmaceutical composition, and has a sufficient sensitivity so that a very small amount of each related substance can be accurately quantified without increasing the injection amount of the sample.